FUNGAL INFECTION

Histoplasmosis

A disease caused by Histoplasma capsulatum, causing primary pulmonary lesions and hematogenous dissemination.

Symptoms and Signs

The disease has three main forms. Acute primary histoplasmosis is usually asymptomatic

Progressive disseminated histoplasmosis follows hematogenous spread from the lungs that is not controlled by normal cell-mediated host defense mechanisms. Characteristically, generalized involvement of the reticuloendothelial system, with hepatosplenomegaly, lymphadenopathy, bone marrow involvement, and sometimes oral or GI ulcerations occurs, particularly in chronic cases

Progressive disseminated histoplasmosis is one of the defining opportunistic infections for AIDS.

Chronic cavitary histoplasmosis is characterized by pulmonary lesions that are often apical and resemble cavitary TB. The manifestations are worsening cough and dyspnea, progressing eventually to disabling respiratory dysfunction. Dissemination does not occur

Diagnosis

Culture of H. capsulatum from sputum, lymph nodes, bone marrow, liver biopsy, blood, urine, or oral ulcerations confirms the diagnosis

CONGESTION

Congestion or hyperaemia means an increase in the content of blood in an organ. It may be :

A. Active - due to increased arterial flow to the organ with dilatation of micro vessels as in

• Inflammation.
• Increased metabolic activity.
• Neurogenic blushing.

B. Passive - due to decreased venous drainage resulting in pooling of blood. There is always an associated element of oedema.

Fungal
 
Superficial mycoses

1. Superficial mycoses→outermost layers of the skin or its appendages; skin, nails and/or hair.
2. Dermatophytoses transmitted by contact with man (anthropophilic; weak inflammatory response), animals (zoophilic; brisk inflammatory response), or contact with soil (geophilic; strongest inflammatory response).
3. Trichophyton→hair, skin, or nails; Microsporum → hair and skin; and Epidermophyton→skin alone.
4. The diagnosis is best made by culture of skin scrapings secured from the leading edge of the lesion.
 - use Wood's light to check for fluorescing metabolites.
 - direct KOH preparations of the scraped material
 
 Subcutaneous Mycoses
 
1. Subcutaneous mycoses are usually related to traumatic implantation into the skin.
2. Chromoblastomycosis, or verrucous (wart-like) dermatitis, is a chronic skin lesion associated with several pigmented fungi (Fonsecaea, Phialophora, and Cladosporium).
 - granulomatous reaction in subcutaneous tissue are pigmented, thick walled bodies are visible in tissue section.
3. Mycetomas (maduromycosis) are characterized by a localized, tumorous nodule (usually foot) that occurs in response to chronic progressive destruction of skin, subcutaneous tissue, fascia, muscle and bone 

4. Sporotrichosis is caused by the dimorphous fungus, Sporothrix schenckii.
 - traumatic implantation of the fungus growing in soil, thus the association with "rose gardeners disease".
 - MC lymphocutaneous disease → painless nodule at inoculation site → chain of suppurating subcutaneous nodules that drain to the skin surface along the course of the lymphatics.

- cigar shaped yeast forms are seen in the suppurative nodules and asteroid bodies (Splendore-Hoeppi phenomenon) are noted within granulomatous microabscesses.
 - treatment: oral potassium iodide

Cartilage-Forming Tumors

1. Osteochondroma (Exostosis) is a relatively common benign cartilage-capped outgrowth attached by a bony stalk to the underlying skeleton. Solitary osteochondromas are usually first diagnosed in late adolescence and early adulthood (male-to-female ratio of 3:1); multiple osteochondromas become apparent during childhood, occurring as multiple hereditary exostosis, an autosomal dominant disorder. Inactivation of both copies of the EXT gene (a tumor suppressor gne) in chondrocytes is implicated in both sporadic and hereditary osteochondromas. Osteochondromas develop only in bones of endochondral origin arising at the metaphysis near the growth plate of long tubular bones, especially about the knee. They tend to stop growing once the normal growth of the skeleton is completed. Occasionally they develop from flat bones (pelvis, scapula, and ribs). Rarely, exostoses involve the short tubular bones of hands and feet.

Pathological features

• Osteochondromas vary from 1-20cm in size.
• The cap is benign hyaline cartilage. 
• Newly formed bone forms the inner portion of the head and stalk, with the stalk cortex merging with cortex of the host bone.
Osteochondromas are slow-growing masses that may be painful. Osteochondromas rarely progress to chondrosarcoma or other sarcoma, although patients with the multiple hereditary exostoses are at increased risk of malignant transformation. 

2. Chondroma 

It is a benign tumor of hyaline cartilage. When it arises within the medullary cavity, it is termed enchondroma; when on the bone surface it is called juxtacortical chondroma. Enchondromas are usually diagnosed in persons between ages 20 and 50 years; they are typically solitary and located in the metaphyseal region of tubular bones, the favored sites being the short tubular bones of the hands and feet. Ollier disease is characterized by multiple chondromas preferentially involving one side of the body. Chondromas probably develop from slowly proliferating rests of growth plate cartilage.

Pathological features 

• Enchondromas are gray-blue, translucent nodules usually smaller than 3 cm.
• Microscopically, there is well-circumscribed hyaline matrix and cytologically benign chondrocytes.
Most enchondromas are detected as incidental findings; occasionally they are painful or cause pathologic fractures. Solitary chondromas rarely undergo malignant transformation, but those associated with enchondromatosis are at increased risk. 

3. Chondrosarcomas are malignant tumors of cartilage forming tissues. They are divided into conventional chondrosarcomas and chondrosarcoma variants. Each of these categories comprises several distinct types, some defined on microscopic grounds & others on the basis of location within the affected bone, for e.g. they are divided into central (medullary), peripheral (cortical), and juxtacortical (periosteal). The common denominator of chondrosarcoma is the production of a cartilaginous matrix and the lack of direct bone formation by the tumor cells (cf osteosarcoma). Chondrosarcomas occur roughly half as frequently as osteosarcomas; most patients age 40 years or more, with men affected twice as frequently as women 

Pathological features 
Conventional chondrosarcomas arise within the medullary cavity of the bone to form an expansile glistening mass that often erodes the cortex. They exhibit malignant hyaline or myxoid stroma. Spotty calcifications are typically present. The tumor grows with broad pushing fronts into marrow spaces and the surrounding soft tissue. Tumor grade is determined by cellularity, cytologic atypia, and mitotic activity. Low-grade tumors resemble normal cartilage. Higher grade lesions contain pleomorphic chondrocytes with frequent mitotic figures with multinucleate cells and lacunae containing two or more chondrocytes. Dedifferentiated chondrosarcomas refers to the presence of a poorly differentiated sarcomatous component at the periphery of an otherwise typical low-grade chondrosarcoma. Other histologic variants include myxoid, clear-cell and mesenchymal chondrosarcomas. Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs. A slowly growing lowgrade tumor causes reactive thickening of the cortex, whereas a more aggressive high-grade neoplasm destroys the cortex and forms a soft tissue mass. There is also a direct correlation between grade and biologic behavior. 
Size is another prognostic feature, with tumors larger than 10 cm being significantly more aggressive than smaller tumors. High-grade Chondrosarcomas metastasize hematogenously, preferentially to the lungs and skeleton.

Osteomyelitis
This refers to inflammation of the bone and related marrow cavity almost always due to infection. Osteomyelitis can be acute or a chronic. The most common etiologic agents are pyogenic bacteria and Mycobacterium tuberculosis.

Pyogenic Osteomyelitis

The offending organisms reach the bone by one of three routes:
1. Hematogenous dissemination (most common)
2. Extension from a nearby infection (in adjacent joint or soft tissue)
3. Traumatic implantation of bacteria (as after compound fractures or orthopedic procedures). Staphylococcus aureus is the most frequent cause. Mixed bacterial infections, including anaerobes, are responsible for osteomyelitis complicating bone trauma. In as many as 50% of cases, no organisms can be isolated. 

Pathologic features 

• The offending bacteria proliferate & induce an acute inflammatory reaction.
• Entrapped bone undergoes early necrosis; the dead bone is called sequestrum.
• The inflammation with its bacteria can permeate the Haversian systems to reach the periosteum. In children, the periosteum is loosely attached to the cortex; therefore, sizable subperiosteal abscesses can form and extend for long distances along the bone surface.
• Lifting of the periosteum further impairs the blood supply to the affected region, and both suppurative and ischemic injury can cause segmental bone necrosis.
• Rupture of the periosteum can lead to an abscess in the surrounding soft tissue and eventually the formation of cutaneous draining sinus. Sometimes the sequestrum crumbles and passes through the sinus tract.
• In infants (uncommonly in adults), epiphyseal infection can spread into the adjoining joint to produce suppurative arthritis, sometimes with extensive destruction of the articular cartilage and permanent disability.
• After the first week of infection chronic inflammatory cells become more numerous. Leukocyte cytokine release stimulates osteoclastic bone resorption, fibrous tissue ingrowth, and bone formation in the periphery, this occurs as a shell of living tissue (involucrum) around a segment of dead bone. Viable organisms can persist in the sequestrum for years after the original infection.
Chronicity may develop when there is delay in diagnosis, extensive bone necrosis, and improper management. 

Complications of chronic osteomyelitis include
1. A source of acute exacerbations
2. Pathologic fracture
3. Secondary amyloidosis
4. Endocarditis
5. Development of squamous cell carcinoma in the sinus tract (rarely osteosarcoma).

Tuberculous Osteomyelitis

Bone infection complicates up to 3% of those with pulmonary tuberculosis. Young adults or children are usually affected. The organisms usually reach the bone hematogenously. The long bones and vertebrae are favored sites. The lesions are often solitary (multifocal in AIDS patients). The infection often spreads from the initial site of bacterial deposition (the synovium of the vertebrae, hip, knee, ankle, elbow, wrist, etc) into the adjacent epiphysis, where it causes typical granulomatous inflammation with caseous necrosis and extensive
bone destruction. Tuberculosis of the vertebral bodies (Pott disease), is an important form of osteomyelitis.

Infection at this site causes vertebral deformity and collapse, with secondary neurologic deficits. Extension of the infection to the adjacent soft tissues with the development of psoas muscle abscesses is fairly common in Pott disease. Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections. Diagnosis is established by synovial fluid direct examination, culture or PCR

Urticaria (hives) refers to the presence of edema within the dermis and itchy elevations of the skin which may relate to either a Type I (MC) or Type III hypersensitivity reaction.

Type III hypersensitivity reaction.

 - exaggerated venular permeability MC related to IgE mediated disease and release of histamine from mast cells.